Certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamides as dipeptidyl peptidase 1 inhibitors

Abstract

The present disclosure relates to certain (2S)-N-[(1S)-1-cyano-2-phenylethyl]-1,4-oxazepane-2-carboxamide compounds (including pharmaceutically acceptable salts thereof),that inhibit dipeptidyl peptidase 1 (DPP1) activity, to their utility in treating and/or preventing clinical conditions including respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), to their use in therapy, to pharmaceutical compositions containing them and to processes for preparing such compounds.

The invention claimed is: 
     
       1. A method for treating alpha-1 antitrypsin deficiency in a patient in need thereof, comprising, administering to the patient, an effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein, 
         R 1  is 
       
       
         
           
           
               
               
           
         
         R 2  is selected from hydrogen, F, Cl, Br, OSO 2 C 1-3 alkyl, or C 1-3 alkyl; 
         R 3  is selected from hydrogen, F, Cl, Br, CN, CF 3 , SO 2 C 1-3 alkyl, CONH 2  or SO 2 NR 4 R 5 , wherein R 4  and R 5  together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or 
         R 1  is selected from 
       
       
         
           
           
               
               
           
         
         X is selected from O, S or CF 2 ; 
         Y is selected from O or S; 
         Q is selected from CH or N; 
         R 6  is selected from C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, or tetrahydropyran; and 
         R 7  is selected from hydrogen, F, Cl or CH 3 . 
       
     
     
       2. The method of  claim 1 , wherein R 1  is selected from 
       
         
           
           
               
               
           
         
         X is selected from O, S or CF 2 ; 
         Y is selected from O or S; 
         Q is selected from CH or N; 
         R 6  is selected from C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, or tetrahydropyran; and 
         R 7  is selected from hydrogen, F, Cl or CH 3 . 
       
     
     
       3. The method of  claim 1 , wherein,
 R 1  is 
 
       
         
           
           
               
               
           
         
         X is selected from O, S or CF 2 ; 
         Y is selected from O or S; 
         R 6  is selected from C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OC 1-3 alkyl, N(C 1-3 alkyl) 2 , cyclopropyl, or tetrahydropyran; and 
         R 7  is selected from hydrogen, F, Cl or CH 3 . 
       
     
     
       4. The method of  claim 1 , wherein,
 R 1  is 
 
       
         
           
           
               
               
           
         
         X is O; 
         R 6  is C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 F; and 
         R 7  is hydrogen. 
       
     
     
       5. The method of  claim 1 , wherein,
 R 1  is 
 
       
         
           
           
               
               
           
         
       
     
     
       6. The method of  claim 4 , wherein,
 R 1  is 
 
       
         
           
           
               
               
           
         
         X is O; 
         R 6  is C 1-3 alkyl; and 
         R 7  is hydrogen. 
       
     
     
       7. The method of  claim 1 , wherein the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-y-l)phenyl]ethyl}-1,4-oxazepane-2-carboxamide 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       8. The method of  claim 7 , wherein the compound of formula (I) is (2S)-N-{(1S)-1-cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-y-l)phenyl]ethyl}-1,4-oxazepane-2-carboxamide 
       
         
           
           
               
               
           
         
       
     
     
       9. The method of  claim 1 , wherein the compound is present in a sterile solution, suspension or emulsion. 
     
     
       10. The method of  claim 7 , wherein the compound is present in a sterile solution, suspension or emulsion. 
     
     
       11. The method of  claim 10 , wherein administering comprises parenteral administration. 
     
     
       12. The method of  claim 11 , wherein the parenteral administration is intravenous, subcutaneous, intramuscular, intravascular or infusion administration. 
     
     
       13. The method of  claim 12 , wherein the parenteral administration is intravenous administration. 
     
     
       14. The method of  claim 1 , wherein administering comprises oral administration. 
     
     
       15. The method of  claim 7 , wherein administering comprises oral administration.